1. Field of the Invention
The present invention relates generally to the field of molecular biology and biochemistry. More specifically, the present invention relates to development of a live vaccine for human immunodeficiency virus (HIV).
2. Description of the Related Art
Vaccines are a most cost-effective treatment of infectious diseases. Successful vaccines have greatly reduced the incidence of measles, mumps, pertussis, rubella, poliomyelitis, tetanus, and small pox. The development of an effective vaccine for HIV is imperative. Estimates from the World Health Organization predict that by the year 2000, 40 million people will be infected with HIV world wide.
A recent evaluation of HIV vaccine development approaches is described by Schultz in Changing Paradigms for an HIV Vaccine (Schultz, 1996). In this article Schultz discusses several paradigms, the first of which is calls “sterilizing immunity”. It was originally believed that in order to prevent AIDS, HIV infection must be completely prevented. The logical method for accomplishing such a goal was to induce high titers of neutralizing antibodies. The only legitimate antigens for such a vaccine are gp120 and gp41, the HIV envelope proteins, which contain neutralizing epitopes. Several general methods were used for developing these vaccines. First, genetically engineered expression systems were used to produce the envelope subunit proteins, gp120 or gp160. The recombinant proteins were then formulated into alum or in novel adjuvants. The second method involved inserting HIV env genes into live vectors such as vaccinia and canarypox. The third approach used peptide epitopes, in an attempt to eliminate irrelevant epitopes, thereby forcing the immune system to focus on the relevant, neutralizing epitopes.
Two additional series of experiments falling under the “sterilizing immunity” paradigm involves research done in non-human primates. Whole-inactivated vaccines are very common and have been very effective. With HIV however, no such study has ever been attempted in humans, primarily due to the grave consequences if viral particles were ever not completely inactivated.
The second paradigm for HIV vaccine development involves concepts not new to vaccine research, but represents a change in approach for dealing with HIV. Rather than initial prevention of infection, an infection begins, but is contained and eventually cleared. A vaccine may be deemed effective if the viral load is rapidly cleared, or reduced to such a level that it no longer produces symptoms, or permits transmission to others (Johnston, 1997). One of the main developments that led to this change in perspective is the fact that blood AIDS virus levels indicate a steady-state balance between daily production and clearance of enormous amounts of HIV (Wei, 1995, Ho, 1995). These findings illustrate that the immune system is nearly successful in defeating the virus but after time finally succumbs to HIV.
Some current research on the HIV virus includes the use of gag gene, protease genes, and parts of the pol gene. Additional work focuses on using pseudovirions, which are a non-infectious and safe form of whole-inactivated virus. One such vaccine is currently in small primate trials. Synthetic peptide vaccines have also been explored and found to induce a cytotoxic T lymphocyte response in mice if conjugated to certain lipid moieties. Human testing is currently underway on some of these peptide products. DNA based vaccines are also being explored, as they are relatively inexpensive and easily produced. Early results indicate good cellular response, as well as strong humoral immunity (Glaser, 1997).
The majority of HIV infections are transmitted via mucosal surfaces. This route of entry strongly suggests that a vigorous mucosal immune response would be desirable. It has traditionally been difficult to elicit such responses at the mucosal surface. Recent work presented at the 9th Annual Meeting of the National Cooperative Vaccine Development Groups for AIDS (May, 1997) by Musey, described the presence of HIV specific cytotoxic T lymphocytes in the mucosa of the genital tract in infected men and women. Mucosal T cells were isolated from male semen samples and female cervical brushings and stimulated with different specific antigens from HIV. Responses were seen to the HIV Env, Gag and Pol proteins. Additional research presented at the same Meeting (May 1997) by Clerici, points to possible protection of uninfected partners by mucosal IgA.
Developing a live vaccine has several advantages over developing a dead vaccine (subunit vaccine). Attenuated strains of bacteria have been genetically manipulated to express virulence antigens from different pathogens. It has been found that several of these bacteria are capable of eliciting both humoral and cellular immune responses not only against the wild type of their species, but also against the pathogen providing the genetic material for the antigen (Curtiss, 1989).
Strains of Salmonella have the ability to bind preferentially to M cells in the intestinal mucosa. While this tactic would normally allow the immune system to mount a response and clear the infection, Salmonella have developed a unique way of evading detection. Once in the mucosa, Salmonella are actually taken up into cells in endosomes, and can remain there undetected. Bacteria have been captured on film dividing inside such endosomes in human cell lines (Sztein, 1995). This adaptation of Salmonella may prove to be very helpful in developing a vaccine. If enough of the attenuated Salmonella can survive inside cells, perhaps this can aid in the establishment of a long-term infection, and result in lasting immunity to the foreign antigens.
Another major benefit of using Salmonella is that the bacteria seem to serve as an adjuvant, resulting in a greater immune response than if the antigen were administered alone. Subunit vaccines, administered alone, often elicit weaker responses, and there are currently few adjuvants that are available for use in humans. Even with the aid of adjuvants, the parenteral delivery of most subunit vaccines fails to induce a secretory response at the mucosal surface, or stimulate a strong T cell response. As mentioned previously, both a strong cell mediated response and mucosal immunity are believed to be important in possibly clearing an HIV infection.
The prior art is deficient in an inexpensive live vaccine for human immunodeficiency virus. The present invention fulfills this long-standing need and desire in the art.